The Ends Have Arrived

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell (Impact Factor: 32.24). 12/2009; 139(6):1038-40. DOI: 10.1016/j.cell.2009.11.033
Source: PubMed

ABSTRACT The 2009 Nobel Prize in Physiology or Medicine has been awarded to Elizabeth Blackburn, Carol Greider, and Jack Szostak for their contributions to our understanding of how the ends of eukaryotic chromosomes, telomeres, are replicated by a specialized reverse transcriptase, telomerase. I present a personal view of the telomere field, putting the contributions of these three Nobel laureates into historical context.

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    • "Telomerase is a unique reverse transcriptase (RT) essential for de novo synthesis of telomeric DNA repeats onto chromosomal termini to counter progressive telomere shortening resulting from incomplete end replication (Zakian, 2009). The renewal capacity of highly proliferative cells, such as germline and stem cells, relies on telomere length maintenance by telomerase to offset cellular and organismal aging. "
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    ABSTRACT: Telomerase synthesizes telomeric DNA repeats onto chromosome termini from an intrinsic RNA template. The processive synthesis of DNA repeats relies on a unique, yet poorly understood, mechanism whereby the telomerase RNA template translocates and realigns with the DNA primer after synthesizing each repeat. Here, we provide evidence that binding of the realigned RNA/DNA hybrid by the active site is an essential step for template translocation. Employing a template-free human telomerase system, we demonstrate that the telomerase active site directly binds to RNA/DNA hybrid substrates for DNA polymerization. In telomerase processivity mutants, the template-translocation efficiency correlates with the affinity for the RNA/DNA hybrid substrate. Furthermore, the active site is unoccupied during template translocation as a 5 bp extrinsic RNA/DNA hybrid effectively reduces the processivity of the template-containing telomerase. This suggests that strand separation and template realignment occur outside the active site, preceding the binding of realigned hybrid to the active site. Our results provide new insights into the ancient RNA/DNA hybrid binding ability of telomerase and its role in template translocation.
    The EMBO Journal 01/2012; 31(1):150-61. DOI:10.1038/emboj.2011.363 · 10.43 Impact Factor
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    • "Since then, it has become apparent that several aspects of telomere biology are relevant to human cancer, offering potential opportunities for clinical intervention. In the work by Blackburn, Greider and Szostak, that was awarded the 2009 Nobel Prize in Physiology and Medicine (Zakian 2009), the structure of the chromosome ends was discovered to be specialized nucleoprotein structures that comprise the ''end zone " of chromosomes, called telomeres. "
    DNA Repair and Human Health, 10/2011; , ISBN: 978-953-307-612-6
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    • "The precise length of each telomere controls the cell's ability to replicate, suggesting a regulatory role for their G-quadruplex structures. In normal cells, the length of the telomeric region is reduced during each round of replication until the Hayflick limit is reached, at which point the cell enters apoptosis (Zakian, 2009). The misregulation of telomerase activity can lead to immortality of cells and associated tumorogensis. "
    DNA Replication-Current Advances, 08/2011; , ISBN: 978-953-307-593-8
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